Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway in the central regulation of reproduction. The experiments described in this proposal aim to test the hypothesis that the activity of GnRH neurons is regulated by metabolic status, and in particular by circulating levels of glucose. This is of practical relevance as blood glucose is elevated in type 2 diabetes and polycystic ovary syndrome (PCOS), two disorders in which fertility is impaired. PCOS is the leading cause of infertility and is characterized centrally by enhanced frequency of GnRH secretion. Stimulatory actions of glucose on GnRH neurons are thought to be important in the pathogenesis of infertility in this disorder. Preliminary data suggest that GnRH neurons are glucose-responsive and express ATP-sensitive potassium (KATP) channels; additionally, they may be regulated by a larger glucose-responsive network via afferent connections from critical energy- sensing brain regions such as the arcuate nucleus. Thus intrinsic and transsynaptic mechanisms for glucose action on GnRH neurons may be important. To investigate these hypotheses, the effects of glucose on GnRH neurons in acutely-prepared brain slices will be examined using extracellular and whole-cell electrophysiological techniques. Furthermore, as androgens are elevated in PCOS and in some women with obesity, the possibility that androgens increase glucose-responsiveness will be tested by determining if androgens alter KATP currents in GnRH neurons from mice with steroid implants. Lastly, using a previously characterized mouse model for PCOS that exhibits elevated circulating androgens, increased central drive to the reproductive system, and impaired glucose tolerance, the interaction of these phenotypes in vivo will be examined in terms of their effects on glucose-responsiveness and KATP current in GnRH neurons. KATP channels are of particular interest as they are expressed in both GnRH neurons and pancreatic beta cells, serving as another possible link between metabolism and reproduction in PCOS. PCOS and diabetes are extremely common disorders with diverse health consequences, and new potential targets for therapeutic intervention must be identified. The studies outlined in this proposal aim to elucidate basic pathophysiologic mechanisms of infertility in these disorders and yield insight into reproductive-metabolic links, with the hope of coming closer to that goal. [unreadable] [unreadable] [unreadable]